Abstract
Purpose
Although the incorporation of research biopsies into clinical trials is increasing, limited information is available about how study protocols and informed consents integrate and describe their use.
Methods
All therapeutic clinical trials in which image-guided research biopsies were performed from January 1, 2005, to October 1, 2010, were identified from an interventional radiology database. Data from study protocols and informed consents were extracted and analyzed. Procedural complications were recorded.
Results
A total of 57 clinical trials were identified, of which 38 (67%) contained at least one mandatory biopsy. The analysis of the research biopsy tumor tissue was a study end point in 95% of trials. The primary indication for a research biopsy was for integral biomarker analysis in 32% and for correlative science in 68% of trials. A statistical analytic plan for the correlative science research biopsy tumor tissue was mentioned in 26%, described as exploratory in 51%, and not mentioned in 23% of trials. For studies with mandatory biopsies, biopsy was an eligibility criterion in 71% of trials, and a statistical justification for the research biopsy sample size was present in 50% of trials. A total of 745 research biopsies were performed on 576 patients. Overall and major complication rates were 5.2% (39 of 745 biopsies) and 0.8% (six of 745 biopsies), respectively. Complication rates for intrathoracic and abdominal/pelvic solid organ biopsies were 17.1% (36 of 211 biopsies) and 1.6% (three of 189 biopsies), respectively. Site-stratified research biopsy–related risks were discussed in five consents.
Conclusion
A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.
INTRODUCTION
Therapeutic clinical trials are integral to cancer drug development. The improved molecular understanding of cancer has led to an increased incorporation of biomarkers into clinical trials. Consequently, there is a burgeoning interest in the use of research biopsies to obtain tumor tissue for patient-driven correlative science.1–3 The analysis of tumor tissue can be used to improve characterization of the pharmacodynamic effects of a drug, identify the molecular processes involved in drug response or resistance, and to identify prognostic and predictive biomarkers.
Because a research biopsy represents an invasive procedure with finite risk and generally no direct benefit to the patient, ethical concerns over the use of research biopsies, especially mandatory biopsies, have been raised.4–8 A consensus statement from a National Cancer Institute (NCI) Cancer Therapy Evaluation Program–sponsored workshop regarding pediatric research recommended that correlative research with no direct benefit to participants should be optional.9 However, some researchers have argued there is a “moral obligation to include correlative biopsies in appropriate clinical trials,” whereas others have argued the use of mandatory biopsies is appropriate when supported by a strong scientific rationale and adequate informed consent (IC).1,2,6 Opinions are clearly divided, and at present, the Eastern Cooperative Oncology Group requires all research biopsies conducted on clinical trials to be optional.10
Despite extensive discussions regarding the ethics of research biopsies, few researchers have attempted to evaluate how the scientific rationale, risks, and benefits of a research biopsy are documented in study protocols (SPs) and ICs for these trials. Because the arguments for research biopsies hinge on the strength of the scientific rationale for the biopsy and the clarity of the IC, data regarding the language used to describe the use of research biopsies in SPs and ICs are needed. The goals of this study were to determine how the scientific rationale for the research biopsy is presented in the SP, to determine whether the nature (mandatory v optional), risks, and benefits of a research biopsy are clearly communicated to the patient, and to assess research biopsy–related complications.
METHODS
Identification of Trials
We searched the University of Texas MD Anderson Cancer Center Interventional Radiology (IR) research biopsy database, which includes all clinical trials that require an image-guided research biopsy from January 1, 2005, to October 1, 2010. The IR section performs all image-guided biopsies with the exception of breast and thyroid biopsies, which were not included in this analysis. In addition, non–image-guided biopsies, such as skin, buccal mucosa, or bone marrow biopsies, were not recorded in this analysis. Of the 73 identified clinical trials, 16 nontherapeutic studies, in which research biopsies were acquired for tissue banking and laboratory research, were excluded from this analysis. A total of 57 therapeutic clinical trials, including at least one image-guided, nondiagnostic research biopsy, were identified and analyzed. For each trial, the most recent SP and IC as of June 15, 2010, was reviewed. The Institutional Review Board (IRB) approved this study.
Evaluation of SPs and ICs
Data was extracted independently by two investigators (M.J.O. and J.M.), and all data were crosschecked by the other investigator. By using the SP, studies were characterized by the type of cancer, phase of study, and study sponsorship (industry, academic, or NCI sponsored). Sponsorship did not necessarily reflect the source of funding for each trial because investigator-initiated clinical trials were classified as academic trials. Other data collected included research biopsy characteristics (mandatory or optional, timing of biopsy, number of biopsy encounters), whether a mandatory research biopsy was specifically listed as an eligibility criterion, and whether the rationale for the research biopsy was incorporated as a study end point by using either explicit (a clear statement incorporating the molecular analysis from a research biopsy) or implied (use of terms pharmacodynamic or biomarker[s]) terminology. In studies that provided translational or exploratory end points, these end points were considered equivalent to secondary end points for classification. A statistical justification for the number of patients to undergo mandatory biopsies was defined by statements regarding either an expected effect size or power calculation for this specific cohort. For correlative science studies, we searched for a clear delineation of the primary one or two biomarkers of interest and for a statistical plan regarding the analysis of the tumor tissue obtained. A statistical plan was defined by either a statement regarding the specific statistical test to be used or statements regarding the exploratory nature of the analysis.
The purpose of the research biopsy was categorized into three groups as follows: integral biomarker, in which the results either determined the assignment to a treatment arm or the eligibility for study enrollment; integrated correlative, in which a specific scientific hypothesis (defined as an explicit inclusion of research biopsy obtained tumor tissue in a study end point) and prespecified statistical analysis for research biopsy obtained tumor tissue were discussed; and exploratory correlative biopsy.11,12 Because biopsies could be performed at multiple time points for different purposes, the highest level of scientific rationale was used to categorize each study (integral biomarker > integrated correlative > exploratory correlative).
ICs were evaluated, and specific information related to the rationale for the research biopsy, the description of the biopsy (defined by the terms research, experimental, or investigational), mandatory versus optional classification, and the described risks were recorded. We also searched for statements that documented the lack of a direct benefit from a research biopsy and discussed the safety or accessibility of the tumor location for biopsy. Because all studies included venipuncture, the word count in the risk discussion for venipuncture was compared with that of the research biopsy.
Evaluation of Research Biopsy–Related Complications
Enrolled patients were identified and crossreferenced with the IR research biopsy database. The electronic medical record was reviewed, and data were collected regarding the biopsy site and complications (R.M. and A.L.T.). Complications were graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 with major and minor complications defined as grade 3 or higher and grade 1 or 2, respectively.
Statistical Methods
Data was analyzed by using statistical software (STATA 12; STATA, College Station, TX). The t test and Fisher's exact test were used to test association between variables. A two-sided P < .05 was considered significant.
RESULTS
Study Characteristics
Study characteristics of the 57 clinical trials are listed in Table 1. Over the study period, 2,218 patients enrolled on these trials with 576 (26%) of these patients undergoing at least one research biopsy. For the 19 studies with only optional biopsies, 58 of 587 enrolled patients (9.9%) underwent a research biopsy. Thirty-eight (67%) of the clinical trials contained mandatory research biopsies. Mandatory biopsies were most commonly restricted to a specific subset of enrolled patients, such as a tumor-specific expansion cohort or a maximum-tolerated dose cohort. Fourteen studies, of which seven studies were phase II or III trials, required mandatory biopsies for all patients.
Table 1.
Study Characteristics (N = 57)*
| Characteristic | No. of Trials | % |
|---|---|---|
| Trial sponsorship | ||
| Industry | 34 | 60 |
| Academia | 17 | 30 |
| NCI sponsored | 6 | 11 |
| Phase of trial† | ||
| I | 33 | 58 |
| I/II | 8 | 14 |
| II | 14 | 25 |
| III | 2 | 4 |
| Cancer type | ||
| Advanced solid tumors | 31 | 54 |
| Breast cancer | 2 | 4 |
| Lymphoma | 6 | 11 |
| Melanoma | 7 | 12 |
| Lung cancer | 7 | 12 |
| Other specific types | 4 | 7 |
| Study classification by type of biopsy | ||
| Mandatory | 38 | 67 |
| Mandatory only | 7 | |
| Mandatory and optional | 31 | |
| Optional | 19 | 33 |
| No. of studies with biopsies during the following time periods | ||
| Pretreatment | 56 | 98 |
| During treatment | 45 | 79 |
| Post-treatment/end of study | 19 | 33 |
| Maximum No. of biopsy encounters per study | ||
| Mandatory | ||
| 0 | 19 | 33 |
| 1 | 16 | 28 |
| 2 | 22 | 39 |
| Optional | ||
| 0 | 7 | 12 |
| 1 | 12 | 21 |
| 2 | 29 | 51 |
| ≥ 3 | 9 | 16 |
| No. of studies requiring mandatory biopsies (n = 38) for | ||
| All patients | 14 | 37 |
| Study subset | 24 | 63 |
| Archival tissue not available | 6 | |
| MTD or expansion cohort | 10 | |
| Both | 8 | |
| No. of studies with optional biopsies (n = 50) for | ||
| All patients | 43 | 86 |
| Study subset | 7 | 13 |
Abbreviations: MTD, maximum-tolerated dose or recommended phase II dose; NCI, National Cancer Institute.
N = 57 is the denominator for percentage calculations unless otherwise specified.
A total of 576 patients underwent a research biopsy. A majority of research biopsies were performed in patients enrolled onto either phase II studies (326 patients; 57%) or phase I studies (206 patients; 36%).
Description of Research Biopsies in SPs
The primary reason for research biopsies was for correlative science in 39 trials (68%; Table 2). Research biopsies were used as an integral biomarker in 18 trials (32%). Integral biomarker studies represented 17% of 2005 to 2007 studies (four of 24 studies) and 42% of 2008 to 2010 studies (14 of 33 studies; P = .05). Integral biomarker studies represented 62% of phase II or III studies but only 20% of phase I or I/II studies, (P = .004). The language used to describe a research biopsy within the SP was inconsistent: Frequently, the term biopsy was used in multiple places within an SP without mention as to whether it was mandatory or optional, and various terms such as “required” or “must be willing to undergo” were used to designate mandatory biopsies.
Table 2.
Inclusion of Research Biopsies in Study Protocols
| Characteristic | Total |
Optional Research Biopsy Studies |
Mandatory Research Biopsy Studies |
|||||
|---|---|---|---|---|---|---|---|---|
| Integral Biomarker |
Correlative Science |
|||||||
| No. | % | No. | % | No. | % | No. | % | |
| Total No. of studies | 57 | 19 | 18 | 20 | ||||
| Research biopsy categorization | ||||||||
| Integral biomarker | 32 | 18 | 0 | 18 | 100 | 0 | ||
| Correlative | 39 | 68 | 19 | 100 | 0 | 20 | 100 | |
| Integrated | 8 | 2 | 0 | 6 | ||||
| Exploratory | 31 | 17 | 0 | 14 | ||||
| Inclusion of biopsy as an eligibility criterion for mandatory biopsy studies, n = 38 | 27 | 71 | NA | 14 | 78 | 13 | 65 | |
| Research biopsy as a study end point* | ||||||||
| Primary | 23 | 40 | 1 | 5 | 14 | 78 | 8 | 40 |
| Secondary | 31 | 54 | 16 | 84 | 4 | 22 | 11 | 55 |
| Not a study end point | 3 | 5 | 2 | 11 | 0 | 1 | 5 | |
| Statistical justification for mandatory research biopsy sample size, n = 38 | 19 | 50 | NA | 13 | 72 | 6 | 30 | |
| Analysis of research biopsy tumor tissue | ||||||||
| Primary molecular marker defined | 28 | 49 | 6 | 32 | 18 | 100 | 4 | 20 |
| Correlative science statistical analysis, n = 39 | 30 | 77 | 15 | 79 | NA | 15 | 75 | |
| Specific statistical test discussed | 10 | 3 | 7 | |||||
| Exploratory† | 20 | 12 | 8 | |||||
Abbreviation: NA, not applicable.
Includes reference to research biopsy, tumor tissue, or specific analyses conducted on research biopsy obtained tumor tissue and terms pharmacodynamic and biomarker.
Includes terms exploratory or descriptive.
The analyses obtained from research biopsies represented a study end point in 54 trials (95%). In 10 of these studies, tumor tissue analyses from research biopsies were not specifically mentioned as an end point but were referenced in the context of a study end point looking at biomarkers or pharmacodynamic markers. A statistical justification for the number of patients to undergo a mandatory research biopsy was present in 19 (50%) of the 38 trials that contained mandatory biopsies. In an additional four protocols, the mandatory research biopsy sample-size cohort was specifically stated as not being based on a statistical justification. For the 39 trials in which the research biopsy was used for correlative science, multiple biomarkers were discussed in 37 trials, but an a priori primary biomarker of interest was identified in only 10 trials. The specific statistical analyses to be conducted on the tumor tissue obtained from the research biopsy were described in 10 trials, noted to be exploratory or descriptive in nature in 20 trials, and absent in nine trials.
No significant differences were detected between academic/NCI-sponsored versus industry-sponsored trials with regard to the incorporation of mandatory research biopsies in protocols (78% v 59%, respectively; P = 1.0), the use of mandatory integral biomarker research biopsies (26% v 35%, respectively; P = .56), or the statistical justification for mandatory research biopsy sample size (60% v 39%, respectively; P = .33).
Description of Research Biopsies in Study ICs
All SPs that included mandatory biopsies had ICs that described a mandatory biopsy. Although the majority of ICs did discuss the rationale for the inclusion of a research biopsy in the clinical trial, almost all ICs failed to provide a specific statement regarding the research nature, alternatives, or lack of benefit to undergoing a research biopsy (Table 3). However, such statements were present in almost all cases regarding participation in the clinical trial as a whole and regarding participation in the optional study procedures within the trial. Statements regarding the restriction of the research biopsy to a safe or accessible site were present in 34 SPs (60%) and 20 ICs (35%). A statement regarding the selection of an accessible biopsy site by a physician was present in 11 (19%) of ICs. The number of biopsy cores or amount of tissue to be taken was mentioned in four ICs (7%) and 15 SPs (26%).
Table 3.
Inclusion of Research Biopsies in Study Informed Consents
| Characteristic | Total |
Optional Research Biopsy Studies |
Mandatory Research Biopsy Studies |
|||||
|---|---|---|---|---|---|---|---|---|
| Integral Biomarker |
Correlative Science |
|||||||
| No. | % | No. | % | No. | % | No. | % | |
| Statement regarding research nature of | ||||||||
| Study | 57 | 100 | 19 | 100 | 18 | 100 | 20 | 100 |
| Biopsy | 12 | 21 | 1 | 5 | 3 | 17 | 8 | 40 |
| Optional procedures* | 52 | 91 | 18 | 95 | 16 | 89 | 18 | 90 |
| Statement regarding lack of benefit from | ||||||||
| Study | 57 | 100 | 19 | 100 | 18 | 100 | 20 | 100 |
| Biopsy | 0 | 0 | 0 | 0 | ||||
| Optional procedures* | 32 | 56 | 14 | 74 | 10 | 56 | 8 | 40 |
| Statement regarding alternatives to undergoing | ||||||||
| Study | 57 | 100 | 19 | 100 | 18 | 100 | 20 | 100 |
| Biopsy | 0 | 0 | 0 | 0 | ||||
| Optional procedures* | 50 | 88 | 19 | 100 | 16 | 89 | 15 | 75 |
| Scientific rationale for biopsy provided | 48 | 84 | 17 | 89 | 17 | 94 | 14 | 70 |
| Statement describing the use of a needle to obtain biopsy† | 38 | 67 | 14 | 74 | 9 | 50 | 15 | 75 |
| Use of image guidance mentioned | 14 | 25 | 1 | 5 | 6 | 33 | 7 | 35 |
| Statement regarding safety or accessibility of biopsy site | 20 | 35 | 8 | 42 | 6 | 33 | 6 | 30 |
Within each informed consent, optional study procedures were listed together and required a separate patient signature.
Includes terms core, fine-needle aspiration, excisional biopsy, needle, or small knife.
A list of discussed risks related to research biopsies is presented in Table 4 . Risks from research biopsies were rarely presented in a site-stratified manner. Two of 57 studies restricted the research biopsy to a specific site (liver or peripheral lymph node). The pneumothorax risk related to an intrathoracic biopsy was discussed in four consents (7%), whereas an intrathoracic biopsy was performed on at least one patient in 17 studies. The mean number of words used in discussing the risks for a research biopsy was less than the number of words used to discuss risks from venipuncture (39 and 48 words, respectively; P < .001).
Table 4.
Discussed Risks of Research Biopsies
| Characteristic | Study Protocol (N = 57) | Informed Consent (N = 57) |
|---|---|---|
| Site-stratified risk discussion | ||
| Lung | 2 | 4 |
| Liver | 3 | 2 |
| Anticoagulation and bleeding risk | 7 | 1 |
| Pain | 2 | 57 |
| Bleeding | ||
| Internal bleeding | 4 | 57 |
| Hypotension/shock | 0 | 57 |
| Infection | ||
| Superficial | 4 | 57 |
| Systemic | 0 | 0 |
| Skin | ||
| Bruising | 0 | 57 |
| Swelling | 0 | 57 |
| Scarring | 0 | 57 |
| Lungs | ||
| Pneumothorax | 2 | 4 |
| Chest tube placement | 0 | 0 |
| Hemoptysis | 0 | 0 |
| Damage to adjacent structures | 2 | 1 |
| Death | 1 | 0 |
Research Biopsy–Related Complications
A total of 745 research biopsies were performed on 576 patients; 169 patients had multiple research biopsy encounters. The overall and major complication rates were 5.2% (39 of 745 biopsies) and 0.8% (six of 745 biopsies), respectively. Complications were directly related to the location of the biopsy (Table 5). The complication rate for intrathoracic biopsies was 17.1% (36 of 211 biopsies), and the complication rate for abdominal and pelvis solid organ biopsies was 1.6% (three of 189 biopsies). Five grade 3 complications, which required either operative intervention or hospitalization, occurred with intrathoracic research biopsies, of which four complications were air-leak complications, and one complication was a postprocedural hypotension with a new onset of atrial fibrillation (Appendix Table A1, online only). An additional grade 3 complication occurred after a liver biopsy in which a large subcapsular hematoma developed, which required embolization of the hepatic artery, patient hospitalization, and a blood transfusion. Of the grade 1 and 2 complications, 31 complications were air-leak complications, and two complications were bleeding complications. When complications from intrathoracic and abdominal and pelvis solid-organ research biopsies were combined, overall and major complication rates were 9.8% (39 of 400 complications) and 1.5% (six of 400 complications), respectively.
Table 5.
Summary of Biopsies and Complications Stratified by Location
| Location | No. of Biopsies (N = 745) | % Total Biopsies Performed | Major Complications [CTCAE grade 3] |
Minor Complications [CTCAE grade 1 or 2] |
||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| Chest-intrathoracic | 211 | 28.3 | 5 | 2.4 | 31 | 14.7 |
| Pulmonary | 177 | |||||
| Mediastinal/hilar | 13 | |||||
| Pleural | 20 | |||||
| Pericardial | 1 | |||||
| Abdomen/pelvis-solid organ | 189 | 25.4 | 1 | 0.53 | 2 | 1.1 |
| Liver | 151 | |||||
| Adrenal | 34 | |||||
| Kidney | 2 | |||||
| Spleen | 1 | |||||
| Uterus | 1 | |||||
| Nonsolid organ | 345 | 46.3 | 0 | 0 | ||
| Head and neck* | 88 | 11.8 | ||||
| Chest-extrathoracic† | 110 | 14.8 | ||||
| Extremities‡ | 11 | 1.6 | ||||
| Abdomen/pelvis-intraperitoneal§ | 34 | 4.6 | ||||
| Abdomen/pelvis-retroperitoneal∥ | 27 | 3.6 | ||||
| Abdomen/pelvis-extraperitoneal∥ | 75 | 10.1 | ||||
NOTE: A coaxial biopsy technique was used in 76% of cases, and a 20-gauge core needle was used in 71% of all biopsies.
Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events.
Included lymph node, parotid gland, scalp, and subcutaneous nodules.
Included lymph node, breast, chest wall, bone, subcutaneous nodules, and muscle.
Included soft tissue masses in upper and lower extremities.
Included omentum, peritoneum, and mesenteric lymph nodes.
Included soft tissue, bone, lymph node, and muscle.
DISCUSSION
Tumor tissue obtained from patients participating in clinical trials represents a valuable research resource and has become an increasingly common component of therapeutic clinical trials.3 This article explores the language used to describe the use of research biopsies in clinical trial SPs and ICs at a single large cancer center and proposes a mechanism by which the representation of risks and benefits of research biopsies can be improved in SPs and ICs.
In the evaluation of how the scientific rationale was presented in the SP, we found the majority of clinical trials included mandatory biopsies and successfully incorporated analyses of research biopsy–obtained tumor tissue in the study end points. However, for nonintegral biomarker studies, we found the statistical analysis that would justify the research biopsy sample size and the statistical methods by which to analyze the biomarker research were frequently absent. In fact, the most common statistical analysis discussed with regard to mandatory correlative research biopsies was exploratory or descriptive. Although external limitations on the number of research biopsy samples are self-evident (ie, maximum-tolerated dose cohort, expansion cohort, or patient acceptance of optional biopsies), the ability to assess the value of the scientific knowledge gained from biomarker analysis of tumor tissue obtained from research biopsies was hindered by the lack of a clear statistical plan.
Guidelines from the Code of Federal Regulations frame the question of the use of research biopsies in clinical trials in what has been termed the Common Rule, which instructs IRBs to ensure that “risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be reasonably expected to result.”13 Although one may assume biomarkers obtained from tumor tissue provide sufficient generalizable knowledge, which has been exemplified by the clinical success of molecular targeting of anaplastic lymphoma kinase in lung cancer and BRAF in melanoma (both represented by trials within this analysis), limited data exist to prove or refute such an opinion.14 In fact, Goulart et al3evaluated 87 phase I studies that used biomarkers obtained from tumor or normal tissue and concluded that biomarkers aided phase II dose selection in only 13% of studies, and the greatest benefit from biomarkers was seen in 39% of trials, in which the biomarkers provided evidence for the proposed mechanism of action of the drug.
To enhance the ability of the IRB to evaluate the strength of the scientific rationale for including a research biopsy in a clinical trial, we propose that a specific section, which clearly outlines the correlative science to be performed on research biopsy–obtained tumor tissue, be incorporated as a standard element of SPs (Table 6). This inclusion would help ensure that both a clear statistical justification and defined scientific question regarding the need for research biopsy–acquired tumor tissue are consistently present in SPs. Furthermore, for clarity and consistency, we recommend standard language (mandatory v optional) be adopted to describe the nature of the research biopsy and an explicit statement regarding the use of safe and accessible tumor tissue be included.
Table 6.
Recommendations for the Adoption of Standard Elements in Study Protocol and Informed Consent Discussing the Use of Research Biopsies in Clinical Trials
| Study Protocol, Research Tumor Biopsy Section | Informed Consent |
|---|---|
| Explicit scientific rationale for the biopsy. | Explicit statement of the research nature of biopsy. |
| Define the hypothesis that tumor tissue will answer and state the tests and statistical analysis to be conducted in the context of a defined or expected number of biopsies. | For nonintegral biomarker studies, an explicit statement of lack of patient benefit from biopsy. |
| In studies with mandatory biopsies, the performance of a biopsy should represent an eligibility criterion. | Site-stratified discussion of tumor biopsy risks. |
| Tumor biopsy clearly labeled by using only mandatory or optional terminology. | Tumor biopsy clearly labeled by using only mandatory or optional terminology. |
| Explicit statement regarding the use of safe and accessible tumor tissue. | Explicit statement regarding the use of safe and accessible tumor tissue. |
The second critical finding from this work compared the conveyed risks and benefits of research biopsies within ICs of these 57 trials to the actual risks observed in the 745 research biopsies performed on study patients from these trials. Previous research efforts have demonstrated that a therapeutic misconception, in which the patient assumes there will be direct benefit from participating in a clinical trial, frequently exists.15–18 The same therapeutic misconception can be extrapolated to the performance of research biopsies. In a self-administered questionnaire regarding the perceptions of mandatory, serial research biopsies, 42% of patients reported that the research biopsy would impact their care, despite the presence of clear statements to the contrary.19 Although the majority of the 57 trials clearly described the research nature, lack of benefit to be expected, and alternatives to undergoing the clinical trial as a whole, these components were not reiterated with regard to the research biopsy itself. The specific delineation and clarity of the language used to represent the research nature and lack of benefit from participation in the clinical trial in each of the 57 ICs represent a conscious and consistent effort by researchers to acknowledge, dispel, and prevent therapeutic misconception from occurring. A similar effort is needed to address research biopsies. We propose that explicit statements describing the research nature and potential lack of benefit in nonintegral biomarker studies be included in ICs (Table 6).
Limited data exist in regards to the risks of research biopsies.20–23 In general, these studies, with the total number of biopsy procedures ranging from 145 to 281 procedures, have shown biopsies to be safe, with complication rates ranging from 0% to 6.2%.21–23 However, none of these studies stratified their analysis of complications by biopsy site. Although the risk of nonsolid organ and abdominal and pelvis solid organ biopsies are low, complications from intrathoracic biopsies occurred in 17.1% of cases, which is a rate similar to previously described rates of 20% to 25% in large series that reported on diagnostic biopsies.24,25 The absence of a statement regarding the risk of pneumothorax for studies in which intrathoracic biopsies were performed represented the greatest discrepancy between the conveyed risks in the ICs and the actual risks. Our data show that stratifying risks by biopsy site can provide valuable information that can be used when discussing potential complications and expectations with the patient. On the basis of similar internal, unpublished data, our institution has recently incorporated a site-stratified risk discussion model into ICs for clinical trials that involve research biopsies.
This study has several limitations. First, despite the large number of clinical trials and research biopsies evaluated, this study represents the experience of a single institution. Second, the review of SPs and ICs focused on the language used, and it is possible that subjective interpretation may not have accurately reflected the true intent of the writer. Last, the study lacked data on the adequacy of the yield from the research biopsies and did not attempt to evaluate the impact of tumor tissue obtained from the research biopsies on the success of the clinical trial or additional development of the experimental agent.
This study demonstrates considerable variation in how SPs describe and justify the scientific rationale of a research biopsy and how ICs discuss associated risks. In an era in which the inclusion of a research biopsy into the clinical trial design is fast becoming the norm, honest and consistent communication with the IRB and patient is essential. Consistent language and explicit statements of intent regarding research biopsies and their associated risks are needed in SPs and ICs.
Acknowledgment
We gratefully acknowledge Sujaya Rao, MS, MHA, for database management support.
Appendix
Table A1.
Summary and Grading of Complications
| Patient No. | Primary Cancer | Body Part | Compartment | Biopsy Location | Type | Target Size (cm) | Image Guidance | Complication | Grading (CTCAE v4.0) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 5 | CT | ptx, prolonged chest tube drainage, and pleurodesis | 3 |
| 2 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | ptx, chest tube, and required admission | 3 |
| 3 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 3 | CT | ptx, chest tube, and required admission | 3 |
| 4 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 3 | CT | Subcutaneous emphysema, chest tube, and required admission | 3 |
| 5 | Thyroid papillary | Chest | Intrathoracic | Pericardium | Soft Tissue | 10 | CT | Hypotension, onset of atrial fibrillation | 3 |
| 6 | Thyroid follicular | Abdomen | Intraperitoneal | Liver | Viscera | 2 | US | Bleeding, subcapsular hematoma and pseudoaneurysm; required embolization, RBC transfusion, and ICU admission | 3 |
| 7 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 5 | CT | ptx and prolonged chest tube (4 d) | 2 |
| 8 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | ptx and chest tube | 2 |
| 9 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 4 | CT | ptx and chest tube | 2 |
| 10 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 4 | CT | ptx and chest tube | 2 |
| 11 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 4 | CT | ptx and chest tube | 2 |
| 12 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 3 | CT | ptx and chest tube | 2 |
| 13 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | ptx and chest tube | 2 |
| 14 | NSCLC | Chest | Intrathoracic | Hilum | Lymph Node | 2 | CT | ptx and chest tube | 2 |
| 15 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 1 | CT | ptx and chest tube | 2 |
| 16 | Melanoma | Chest | Intrathoracic | Lung | Viscera | 3 | CT | ptx and chest tube | 2 |
| 17 | Melanoma | Chest | Intrathoracic | Lung | Viscera | 4 | CT | ptx and chest tube | 2 |
| 18 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | ptx and chest tube | 2 |
| 19 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | ptx and chest tube | 2 |
| 20 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 3 | CT | ptx and chest tube | 2 |
| 21 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 4 | CT | ptx, chest tube | 2 |
| 22 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 3 | CT | Stable ptx and no chest tube | 1 |
| 23 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 5 | CT | Stable ptx and no chest tube | 1 |
| 24 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 4 | CT | Stable ptx and no chest tube | 1 |
| 25 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 8 | CT | Stable ptx and no chest tube | 1 |
| 26 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 5 | CT | Stable ptx and no chest tube | 1 |
| 27 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | Stable ptx and no chest tube | 1 |
| 28 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 4 | CT | Stable ptx and no chest tube | 1 |
| 29 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | Stable ptx and no chest tube | 1 |
| 30 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 8 | CT | Stable ptx and no chest tube | 1 |
| 31 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 3 | CT | Stable ptx and no chest tube | 1 |
| 32 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 16 | CT | Stable ptx and no chest tube | 1 |
| 33 | NSCLC | Chest | Intrathoracic | Lung | Viscera | 2 | CT | Stable ptx and no chest tube | 1 |
| 34 | Adenoid cystic | Chest | Intrathoracic | Lung | Viscera | 3 | CT | Stable ptx and no chest tube | 1 |
| 35 | Melanoma | Chest | Intrathoracic | Lung | Viscera | 3 | CT | Stable ptx and no chest tube | 1 |
| 36 | Breast | Chest | Intrathoracic | Lung | Viscera | 2 | CT | Stable ptx and no chest tube | 1 |
| 37 | Breast | Chest | Intrathoracic | Lung | Viscera | 3 | CT | Stable ptx and no chest tube | 1 |
| 38 | Breast | Abdomen | Intraperitoneal | Liver | Viscera | 4 | U/S | Postbiopsy perihepatic fluid collection | 1 |
| 39 | Neuroendocrine | Abdomen | Intraperitoneal | Liver | Viscera | 4 | U/S | Bleeding | 1 |
Abbreviations: CT, computed tomography; CTCA v4.0, Common Terminology Criteria for Adverse Events version 4.0; ICU, intensive care unit; ptx, pneumothorax; NSCLC, non–small-cell lung cancer; U/S, ultrasound.
Footnotes
See accompanying editorial on page 1
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Michael J. Overman, Alda L. Tam
Financial support: Michael J. Overman
Administrative support: James L. Abbruzzese
Collection and assembly of data: Michael J. Overman, Janhavi Modak, Ravi Murthy, Alda L. Tam
Data analysis and interpretation: Michael J. Overman, Janhavi Modak, Scott Kopetz, James C. Yao, Marshall E. Hicks, James L. Abbruzzese, Alda L. Tam
Manuscript writing: All authors
Final approval of manuscript: All authors
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